August 5th

The tip of an immune molecule known for its ability to fight cancer may also help patients survive pneumonia, scientists report. A synthesized version of the tip of tumor necrosis factor (TNF) (see image) appears to work like a doorstop to keep sodium channels open inside the air sacs of the lungs so excess fluid can be cleared, according to a study published online on July 16, 2014 in the American Journal of Respiratory Critical Care Medicine. This TIP peptide is attracted to the sugar coating at the mouth of the sodium channel. Once the two connect, they move inside the small but essential number of cells that help keep the lungs clear by taking up sodium, said Dr. Rudolf Lucas, vascular biologist at the Medical College of Georgia (MCG) at Georgia Regents University and the study's corresponding author. Inside these cells, TIP binds to the most critical part of the sodium pump, the alpha subunit, and fluid starts moving again. Sodium comes in the channel, water follows, and the sodium pump pushes the fluid into the body's natural drainage network, called the lymphatic system. "The more sodium you take up, the more water will be taken up by these cells," Dr. Lucas said. "That is the way it's supposed to work.” Fluid in the lungs' 266 million air sacs interferes with breathing as well as the important transfer of oxygen from air sacs to capillaries so it can be distributed throughout the body. TNF, known for its tumor-killing capacity, actually has been viewed as a "bad guy" in the lungs where it can block the sodium channel. In fact, excessive TNF production can put patients into shock. "We found that there is another side on the tip of this molecule, which recognizes sugar groups and this side counteracts that side," Dr. Lucas said.

A triple therapy for glioblastoma, including two types of immunotherapy and targeted radiation, has significantly prolonged the survival of mice with these brain cancers, according to a new report by scientists at the Johns Hopkins Kimmel Cancer Center. Mice with implanted, mouse-derived glioblastoma cells lived an average of 67 days after the triple therapy, compared with mice that lasted 24 days when they received only the two immunotherapies. Half of the mice who received the triple therapy lived 100 days or more and were protected against further tumors when new cancer cells were re-injected under the animals' skins. The combination treatment described in an open-access article published on July 11, 2014 in PLOS ONE consists of highly focused radiation therapy targeted specifically to the tumor and strategies that lift the brakes and activate the body's immune system, allowing anti-cancer drugs to attack the tumor. One of the immunotherapies is an antibody that binds to and blocks an immune checkpoint molecule on T cells called CTLA-4, allowing the T-cells to infiltrate and fight tumor cells. The second immunotherapy, known as 4-1BB, supplies a positive "go" signal, stimulating anti-tumor T cells. None of the treatments are new, but were used by the Johns Hopkins team to demonstrate the value of combining treatments that augment the immune response against glioblastomas, the most common brain tumors in human adults. The prognosis is generally poor, even with early treatment. "We're trying to find that optimal balance between pushing and pulling the immune system to kill cancer," said Charles Drake, M.D., Ph.D., an associate professor of oncology, immunology, and urology, and medical oncologist at the Johns Hopkins Kimmel Cancer Center.

August 4th

Researchers from Boston University School of Medicine (BUSM) report that two rare variants in the AKAP9 gene significantly increase the risk of Alzheimer's disease (AD) in African-Americans. This previously unknown association furthers the understanding of the role of genetic factors in the development of AD, according to the researchers, whose findings appeared in the July 2013 issue of Alzheimer's & Dementia. AD is the most frequent age-related dementia affecting 5.4 million Americans including 13 percent of people age 65 and older and more than 40 percent of people age 85 and older. Up to 75 percent of AD cases are thought to have a genetic basis; however the specific genes involved likely differ between ethnic populations. The most well-known AD risk gene, APOE4, does not play as strong a role in AD risk in African-Americans as it does in Caucasians, despite the fact that a higher proportion of African-Americans than Caucasians are afflicted with this disorder. By analyzing the DNA sequence for all genes from participants of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and Genetic and Environmental Risk Factors for Alzheimer's Disease among African-Americans (GenerAAtions) Study, researchers identified two genetic variants in AKAP9 unique to African-Americans that are enriched in individuals with AD. They then confirmed this association in several thousand other African American subjects in the Alzheimer Disease Genetics Consortium dataset. Carriers of either of these AKAP9 variants have a respective 2.8 and 3.6 times greater risk of developing AD. According to the researchers, AKAP9 encodes a protein with multiple forms, One of these, AKAP450, is expressed in the brain and responsible for microtubule anchoring and organization.

Scientists at the University of Maryland (UMD) have developed a new, web-based tool that enables researchers to quickly and easily visualize and compare large amounts of genomic information resulting from high-throughput sequencing experiments. The free tool, called Epiviz, was described in a paper published online on August 3, 2014 in the journal Nature Methods. Next-generation sequencing has revolutionized functional genomics. These techniques are key to understanding the molecular mechanisms underlying cell function in healthy and diseased individuals and the development of diseases like cancer. Data from multiple experiments need to be integrated, but the growing number of data sets makes a thorough comparison and analysis of results challenging. To visualize and browse entire genomes, graphical interfaces that display information from a database of genomic data—called "genome browsers"—were created. Epiviz offers a major advantage over browsers currently available: Epiviz seamlessly integrates with the open-source Bioconductor analysis software widely used by genomic scientists, through its Epivizr Bioconductor package. "Prior tools limited visualization to presentation and dissemination, rather than a hybrid tool integrating interactive visualization with algorithmic analysis," says Dr. Héctor Corrada Bravo, assistant professor in computer science at UMD. He also has an appointment in the Center for Bioinformatics and Computational Biology of the University's Institute for Advanced Computer Studies.

For many animals, making sense of the clutter of sensory stimuli is often a matter of literal life or death. Exactly how animals separate objects of interest, such as food sources or the scent of predators, from background information, however, remains largely unknown. Even the extent to which animals can make such distinctions, and how differences between scents might affect the process were largely a mystery – until now. In a new study, described in an August 3, 2014 online paper in Nature Neuroscience, a team of researchers led by Dr. Venkatesh Murthy, Professor of Molecular and Cellular Biology at Harvard University, showed that while mice can be trained to detect specific odorants embedded in random mixtures, their performance drops steadily with increasing background components. The team also included Drs. Dan Rokni, Vikrant Kapoor, and Vivian Hemmelder, all from Harvard University. "There is a continuous stream of information constantly arriving at our senses, coming from many different sources," Dr. Murthy said. "The classic example would be a cocktail party – though it may be noisy, and there may be many people talking, we are able to focus our attention on one person, while ignoring the background noise. "Is the same also true for smells?" he continued. "We are bombarded with many smells all jumbled up. Can we pick out one smell "object" – the smell of jasmine, for example, amidst a riot of other smells? Our experience tells us indeed we can, but how do we pick out the ones that we need to pay attention to, and what are the limitations?" To find answers to those, and other, questions, Dr. Murthy and colleagues turned to mice. After training mice to detect specific scents, researchers presented the animals with a combination of smells – sometimes including the "target" scent, sometimes not.

August 3rd

A large DNA analysis of people with and without pancreatic cancer has identified several new genetic markers that signal increased risk of developing the highly lethal disease, report scientists from Dana-Farber Cancer Institute (http://www.dana-farber.org/) in Boston. The markers are variations in the inherited DNA code at particular locations along chromosomes. Several of these variations in the DNA code were identified that influence an individual's risk for pancreatic cancer. The discovery of these markers – along with four that were previously identified is important for several reasons, said Brian Wolpin, M.D., M.P.H, first author of the report published online on August 3, 2014 by Nature Genetics. One is that further study of these DNA variants may help explain on the molecular level why some people are more or less susceptible to pancreatic cancer than the average person. A second is the potential to identify people at increased risk who then might be candidates to undergo MRI or ultrasound scanning to look for early, treatable pancreatic tumors. "Currently there is no population screening program for pancreatic cancer, which in 80 percent of cases is discovered when it's too late to allow curative surgery – the cancer has already spread," said Dr. Wolpin. The only healthy individuals currently screened for pancreatic cancer are members of high-risk families due to multiple family members with pancreatic cancer. "But the field has been struggling to find factors that can identify people at highest risk in the general population, when a strong family history is not present," Dr. Wolpin said. The study findings represent analyses of DNA from 7,683 patients with pancreatic cancer and 14,397 control patients without this cancer, all of European descent, from the United States, Europe, Canada, and Australia.

CHARGE, which affects 1 in 10,000 babies, is an acronym whose letters stand for some of the more common symptoms of the condition: coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness. Originally, the researchers were examining the tumor-suppressive properties of the protein, called p53, not investigating developmental disorders. But when a mouse model developed a strange set of deficiencies, the researchers followed a trail of clues that led them to link p53 with CHARGE syndrome. "It was a very big surprise and very intriguing," said Jeanine Van Nostrand, Ph.D., lead author of a paper describing the research and a former Stanford graduate student, now at The Salk Institute for Biological Studies. "p53 had never before been shown to have a role in CHARGE." The paper was published online on August 3, 2014 in Nature. The senior author is Laura Attardi, Ph.D., professor of radiation oncology and of genetics. The researchers originally created a mouse model that expressed a mutated form of the protein, known as p53, to investigate the behavior of p53 in suppressing tumors. Mice expressing only the mutated protein survived. But to the team’s surprise, heterozygous mice, or those with one copy of the mutated p53 and one normal copy, developed symptoms of CHARGE and died in utero. p53 is a cellular quality-control regulator. When it spots an ailing cell, it triggers other proteins to kill the cell or arrest its division. In a developing human or mouse, other proteins switch off p53 so it doesn't inadvertently kill important cells. The mutated form of p53 created by the researchers had a disabled off-switch, but it also couldn't communicate with other proteins to spark the cellular death.

Scientists at Albert Einstein College of Medicine of Yeshiva University have found that bacteria that aid in digestion help keep the intestinal lining intact. The findings, reported online on July 24, 2014, 2014 in the journal Immunity, could yield new therapies for inflammatory bowel disease (IBD) and a wide range of other disorders. The research involved the intestinal microbiome, which contains some 100 trillion bacteria. The role of these microorganisms in promoting or preventing disease is a major emerging field of study. Einstein scientists found that absorption of a specific bacterial byproduct is crucial for maintaining the integrity of the intestinal epithelium—the single-cell layer responsible for keeping intestinal bacteria and their toxins inside the gut and away from the rest of the body. Breaching of the intact intestinal epithelium is associated with a number of diseases. "Intestinal bacteria secrete a wide variety of chemicals known as metabolites," said Sridhar Mani, M.D., co-corresponding author of the paper. "These bacteria and their metabolites were known to influence the intestinal epithelium's integrity, but precisely how they did so wasn't known." Dr. Mani is professor of medicine and of genetics and the Miriam Mandel Faculty Scholar in Cancer Research at Einstein and attending physician, oncology at the Montefiore Einstein Center for Cancer Care and Montefiore Medical Center. Dr. Mani and his colleagues suspected that bacterial metabolites exert their influence by binding to and activating a protein in the nuclei of intestinal epithelial cells called the pregnane X receptor (PXR). PXR was known to be activated by chemicals within the body (such as bile acids) as well as by drugs including steroids and antibiotics.

University of Iowa (UI) researchers have created the most detailed map to date of the abundance of thousands of proteins in the choroid, a region of the human eye long associated with blinding diseases. By seeing differences in protein abundance, the researchers can begin to figure out which proteins may be the critical actors in vision loss and eye disease. Understanding eye diseases is tricky enough. Knowing what causes them at the molecular level is even more confounding. Now, University of Iowa researchers have created the most detailed map to date of a region of the human eye long associated with blinding diseases, such as age-related macular degeneration. The high-resolution molecular map catalogs thousands of proteins in the choroid, which supplies blood and oxygen to the outer retina, itself critical in vision. By seeing differences in the abundance of proteins in different areas of the choroid, the researchers can begin to figure out which proteins may be the critical actors in vision loss and eye disease. “This molecular map now gives us clues why certain areas of the choroid are more sensitive to certain diseases, as well as where to target therapies and why,” says Dr. Vinit Mahajan, assistant professor in ophthalmology at the UI and corresponding author on the paper, published online on July 24, 2014 in the journal JAMA Ophthalmology. “Before this, we just didn’t know what was where.” What vision specialists know is many eye diseases, including age-related macular degeneration (AMD), are caused by inflammation that damages the choroid and the accompanying cellular network known as the retinal pigment epithelium (RPE). Yet they’ve been vexed by the anatomy: Why does it seem that some areas of the choroid-RPE are more susceptible to disease than others, and what is happening at the molecular level?

The brain plays a central role in regulating appetite and whole-body metabolism. A protein known as PPARgamma is important in the brain's control of food intake and body weight, but the identity of the neurons regulating this process has been unclear. A new study published online on August 1, 2014 in the Journal of Clinical Investigation demonstrates that PPARgamma activity in a type of neuron known as pro-opiomelanocortin (POMC) neurons is critical in mediating the response to high-fat diet. Sabrina Diano, Ph.D., and colleagues at Yale University School of Medicine found that mice lacking PPARγ specifically in POMC neurons gained less weight, were more active, and had improved glucose metabolism when fed a high-fat diet. Moreover, animals without PPARgamma in POMC neurons did not gain weight when given PPARgamma activators. The results of this study indicate that PPARgamma expression in POMC neurons regulates whole-body energy balance. The findings also shed light on why PPARgamma activators, which are used clinically to increase insulin sensitivity in patients with type 2 diabetes, have a side effect. Image shows PPAR gamma bound to DNA. [Press release] [Journal of Clinical Investigation article]